This long standing RO1 explores epigenetic abnormalities underlying the initiation and progression of colorectal cancer (CRC), the third most common cause of cancer deaths in the US (U.S. Cancer Statistics Working Group). We are now defining novel perspectives for CRC evolution concerning the presence and position of epigenetic changes, key causes for how they arise and are maintained, and a new understanding of the functional significance of the transcriptional abnormalities for the genes affected. During the last funding cycle, we have integrally linked all of the above with environmental stresses underlying the earliest steps in CRC tumorigenesis. These tie resulting epigenetic abnormalities to the highest CRC risk states, chronic inflammation and especially aging. The above epigenetic dynamics intersect with, and may be obligatory for key genetic alterations to drive the evolution of CRC. An integrating molecular paradigm for all of the above concerns our defining, during the present funding cycle, a novel potential role for recruiting components of the NURD transcriptional repression complex to chromatin as triggered by reactive oxygen species (ROS) exposure and resultant DNA damage . Experimentally, this can associate with initiation and maintenance of abnormal gene expression associated with enhancer and gene promoter DNA methylation. In this proposal, we make novel use of colon organoids to model how the above DNA damage dynamics can underlie epigenetic abnormalities, which allow addiction to key genetic driver mutations to foster colon CRC risk including that associated with aging. Finally, we utilize the molecular events in the above risk paradigm for defining novel targets for reversing abnormal epigenetic gene silencing during CRC initiation and progression. Our proposed studies are then important for derivation of new strategies for prevention, interception, and therapy for CRC. All of the work in our proposal has the potential to define strategies for CRC prevention, interception and therapy underpinned by a novel relationship of the emerging data to the age-risk for these cancers.